The present invention is directed to long-acting coated and controlled release unit dose formulations of 2-[(3-chlorophenyl)amino] phenylacetic acid (23CPPA) for the treatment of glycation-related complications of diabetes. More particularly, it has been discovered that intestinal absorption of the drug is necessary to preclude gastric irritation and accelerated absorption leading to high blood levels in excess of therapeutic concentrations, that the desired therapeutic concentration of 23CPPA that meets drug-to target relationships is in the range of only 10% of that predicted by stoichiometric relationships, that only a small fraction of the albumin in the circulation undergoes nonenzymatic glycation during a 24 hour period, that maintenance of therapeutic blood levels after oral administration of 23CPPA is achieved in extended release pharmaceutical dosage forms, and that long-acting and controlled release unit dose formulations provide delivery of blood concentrations of the drug that are in the therapeutic range of 5,000 to 20,000 ng/ml and that meet drug-to-target relationships with respect to the rate of nonenzymatic glycation of albumin.
The present invention provides formulations of 23CPPA that deliver the compound for absorption in the intestine, that slow and extend the release of 23CPPA, that retard absorption and prolong residence time of 23CPPA in the circulation, and that deliver blood concentrations of the drug that are in the therapeutic range. The present invention also provides once-a-day formulations of 23CPPA that comprise a tablet formulation with an enteric coating that deliver the compound over an extended period of time along the length of the intestinal tract. As used herein, the term 23CPPA includes the free base form and pharmaceutically acceptable salts of 23CPPA such as 23CPPA potassium salt.
23CPPA is an anti-glycation agent that impedes the condensation of free glucose with albumin in a reaction known as nonenzymatic glycation, thereby decreasing the formation of albumin modified by Amadori glucose adducts (U.S. Pat. No. 6,355,680). 23CPPA lowers the concentration of albumin modified by Amadori glucose adducts, even in the presence of marked hyperglycemia, and lessens the pathophysiologic effects of Amadori-modified glycated albumin (AGA) in living organisms (Cohen et al, Kid Int 61:2025-2032, 2002; 68:1554-1566, 2005; AJP Renal 292:789-795, 2007). Experimental studies have causally linked elevated concentrations of albumin modified by Amadori glucose adducts to the pathogenesis of diabetic kidney disease, and have shown that inhibiting the formation of AGA with 23CPPA ameliorates the structural and functional changes associated with diabetic nephropathy and the development of renal insufficiency (Cohen et al, Kid Int 61:2025-2032, 2002; 68:1554-1566, 2005; AJP Renal 292:789-795, 2007), demonstrating that this compound is useful in the treatment of this condition and in arresting progression to renal failure.
23CPPA does not have the molecular formula of a nonsteroidal anti-inflammatory drug (NSAID), and is not an isomer or enantiomer of a NSAID, which are drugs that inhibit the cyclooxygenase (COX) enzymes COX-1 and COX-2. Because 23CPPA is not a pharmacologic inhibitor of the COX-1 or COX-2 enzymes, it does not have the ulcerogenic properties that arise from the COX enzyme inhibitory activity of NSAIDs and is not expected to cause gastric irritation or ulcerogenesis. However, since the pKa (logarithm of the acid dissociation constant) of pharmaceutically acceptable salts of 23CPPA such as potassium is 4.0, hydrogen replaces the potassium at the lower pH that prevails in the intense acid environment of the stomach and the compound becomes a carboxylic acid, which can cause local irritation to the stomach. The acid environment of the stomach also can cause 23CPPA to precipitate out of solution and come into direct and concentrated contact with the stomach lining and cause irritation. The unexpected demonstration that 23CPPA exhibits properties of gastric irritation make it desirable, as disclosed in the present invention, to bypass the stomach in delivery of the drug to the circulation by oral administration.
23CPPA relies on interaction with albumin in the circulation to effectuate its anti-glycation activity, and does not require stoichiometric concentration ratios of drug-to-enzyme for therapeutic efficacy as do the NSAIDs. However, since the concentration of albumin in the blood is approximately 4.5 grams per deciliter liter and the plasma volume is approximately 4 liters, representing a total of approximately 2600 micromoles of albumin in the circulation at a concentration of 660 nmoles per milliliter, it would be expected that on a molar basis an amount of 23CPPA at least equivalent to the amount of albumin would be required to fill the sites with which 23CPPA interacts. However, the unexpected finding that about 10% of that amount is sufficient to fill available sites which interact with 23CPPA enables development of formulations that deliver into the circulation lesser but nevertheless clinically effective concentrations of 23CPPA during an extended period of time.
Since 23CPPA interacts with plasma albumin to effectuate anti-glycation activity, it would be expected that a concentration of drug equivalent to the circulating concentration of albumin and/or glucose would be required in impede the condensation of free glucose with the albumin protein. However, the unexpected finding that less than one percent of circulating albumin is nonenzymatically glycated during a 24 hour period, even at glucose concentrations eight-fold higher than the physiologic range such as can be found in people with diabetes, enables development of long-acting and controlled release dosage formulations that can deliver blood concentrations of 23CPPA over a 24 hour period that match drug-to target relationships with respect to the rate of nonenzymatic glycation of albumin during that period of time.
The present invention therefore addresses the existing need for preparations of 23CPPA that are capable of eliciting the desired effect in the safest and most efficacious manner and that deliver the drug over a period compatible with clinical requirements by the disclosure of preparations of 23CPPA that achieve these aims by delivering the drug to the intestinal tract, slowing its dissolution, extending its release over a prolonged period of time, and delivering concentrations of the drug to the blood that meet drug-to-target relationships with respect to sites available for binding to 23CPPA.
Additionally, the formulations of the present invention avoid patient non-compliance with omission of prescribed dosings necessary for optimum clinical control attendant to the nuisance of multiple daily dosings.